phenethyl_man

The preparation of both the 1-methyl ether [1] and 1,2-dimethyl ether [2] by the action of dimethyl sulfate on pyrogallol have been well described here. The former being prepared by blockage of two of the hydroxyl groups by boric acid using excess DMS, and the second being prepared by carboxylation to pyrogallolcarboxylic acid, methylation and subsequent decarboxylation.

However, the only preparation I could find of the 1,3-dimethyl ether involves the use of gaseous methyl bromide and NaOMe [3]. Can anyone explain the mechanism behind this reaction so perhaps we can come up with a workable synthesis using DMS?

Obviously my interest in this compound is that just about any formylation procedure will prepare syringaldehyde from this compound which can lead 3,4,5-substituted phenethylamines; whereas any other pyrogallic ether will inevitably result in a useless 2,3,4-substitution pattern.

Rhodium posted what is seemingly a preparation of this ether (also known as 2,6-dimethoxyphenol) in

moo

However, the only preparation I could find of the 1,3-dimethyl ether involves the use of gaseous methyl bromide and NaOMe [3]. Can anyone explain the mechanism behind this reaction so perhaps we can come up with a workable synthesis using DMS?

NaOMe is the base used to deprotonate the phenolic hydroxyls, making them good nucleophiles. The reaction is an SN2 type nucleophilic substitution reaction, bromide being the leaving group. Reaction with DMS is goes through the same mechanism.

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phenethyl_man

I know how nucleophilic substitution works, I was just questioning the use of such a strong base in this particular reaction when alkali carbonates and hydroxides are strong enough to deprotonate phenols and if the rapid gassing w/MeBr has any effect on what gets alkylated.

The problem is trying to obtain a good yield of the 1,3-dimethyl ether. Does this substitution follow any rules to predict which hydroxyl will be methylated first, second? Will methylation of pyrogallol w/2 mol eq. DMS produce primarily syringol, or should I assume both methyl groups are displaced and use 1 mol eq DMS? Will the outer phenolic groups be alkylated first or does it just proceed at random?

Any 2,3,4-trimethoxybenzene can be easily removed from the alkaline soln containing the phenolates, but how is one to seperate any unreacted pyrogallol, 1-methyl ether, or 1,2-dimethyl ether that is formed from the desired product. And what is the optimal way to run the rxn to optimize the yield of the desired phenol.

I suppose it is because 2,6-dimethoxyphenol is such a readily available material commercially that no one cares to synth it themselves but it is strange I can't find any information relating to the production of it; most likely doesn't even use pyrogallol as a precursor.

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moo

To my knowledge the 2-hydroxyl is least acidic of the three, so the hydroxyls at 1- and 3-position are the ones deprotonated first, enabling them to be methylated. Theoretically one needs two equivalents of a base for this, but the authors use 2,5 equivalents of sodium methoxide instead. There is also the possibility of Williamson ether synthesis side reaction, MeBr + NaOMe --> Me2O + NaBr, so I quess the extra half equivalent is used to compensate for that side reaction.

Also note that no yield is given and that the product is purified by vacuum distillation. What else is there produced? Some 1,2,3-trimethoxybenzene prehaps?

I don't actually know if using DMS is viable in practice, theoretically it should be. Sodium hydroxide should be enough to deprotonate the hydroxyls. I reckon there are other methods out there, waiting to be digged up from the library.

Edit: I noticed one more thing so there is one correction to what I said. The methoxide is added simultaneously with the methyl bromide. This is most likely an attempt to not deprotonate two phenolic hydroxyls at once, but to keep to situation such that only phenolate monoanions are present in the solution, so that pyrogallol first gets methylated at the 1-hydroxyl, and the 1-methoxy-2,3-dihydroxybenzene (whose 3-hydroxyl is the most acidic one) formed is then methylated to 2,6-dimethoxyphenol. Stepwise methylation.

phenethyl_man

Also note that no yield is given and that the product is purified by vacuum distillation. What else is there produced? Some 1,2,3-trimethoxybenzene prehaps?

yeah, it states that the 1,2,3-trimethoxybenzene is steam distilled off before the oil is fractionated. I assume the trimethyl ether is volatile with steam while the others are not. The fact that it is an oil implies there is some impurity besides a pyrogallic ether since all possible ethers of pyrogallol are solids. His b.p is also 11 degC off from most of the literature I have, but since this was almost a century ago I guess I'll give him a break

Here is the exact wording from the document, perhaps it is a little more clear than the trunicated rendition on rhodium, however, still no sign of a yield:

Pyrogallol Dimethyl Ether Sulfonic Acid.-

The preparation of pyrogallol 1,3-dimethyl ether involves considerable difficulty if attempted by the usual methods. The use of an autoclave and the oxidizing influence of the air can be avoided by the following method:

One mol. pyrogallol is placed in a flask connected with a reflux condenser. Methyl bromide is passed into the flask by a glass tube ending in a capillary and passing through the condenser to near the bottom of the flask until the air is displaced.

Two and a half mols. metallic sodium are dissolved in twenty mols. methyl alcohol absolute. This sodium alcoholate is run into the flask together with a continuous stream of methyl bromide. The flask is heated on the water bath and the current of alkyl halide continued until the reaction is nearly neutral. The gas is rapidly absorbed and sodium bromide settles out.

The methyl ether is isolated as follows: Water is added until the sodium bromide dissolves. The methyl alcohol is then evaporated and the residue distilled in steam. Any trimethyl ether passes over in the steam. The dimethyl ether is extracted with ether after acidifying. The ether solution is evaporated and the resulting oil fractionated in vacuo. A Colorless liquid boiling at 250 degC was obtained. To check the purity the methyl-ether content was determined and 40.42% : 40.31% found while the theoretical figure is 40.26%. Further methylation by the above method yields the trimethyl ether.

Not quite sure what they mean by "methyl-ether content."

Edit: I noticed one more thing so there is one correction to what I said. The methoxide is added simultaneously with the methyl bromide. This is most likely an attempt to not deprotonate two phenolic hydroxyls at once, but to keep to situation such that only phenolate monoanions are present in the solution, so that pyrogallol first gets methylated at the 1-hydroxyl, and the 1-methoxy-2,3-dihydroxybenzene (whose 3-hydroxyl is the most acidic one) formed is then methylated to 2,6-dimethoxyphenol. Stepwise methylation.

So I guess the key is to try to keep the reaction mixture as close to neutral as possible through out the reaction which will cause only one hydroxyl to be deprotonated at any given time?

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moo

Methyl ether content means that they have determined the amount of methoxy groups per mass unit with some analytical method. The presence of pyrogallol monomethyl ether lowers this figure while trimethyl ether raises it and 2,3-dimethoxyphenol doesn't make a difference and so on. When you calculate the molar mass of two methoxyl groups (CH3-O-), divide it by the molar mass of 2,6-dimethoxyphenol and multiply the result by 100% you get 40,26%, the theoretical figure. That's how they did things before modern analytical equipment.

So I guess the key is to try to keep the reaction mixture as close to neutral as possible through out the reaction which will cause only one hydroxyl to be deprotonated at any given time?

Captain_America

I haven't read whole this thread but I guess you want to go to 3,4,5 pattern with this starting material. You can formylate this compound in 100% street fashion, getting syringaldehyde, the yields are pretty bad, it is IMO not a good route, but you can alternatively go from vanillin of course also OTC;

A well-stirred (Note 1) and (Note 2) mixture of 740 ml. of glycerol and 216 g. of boric acid, in a 2-l. three-necked round-bottomed flask fitted with a thermometer and a condenser for downward distillation, is dehydrated by heating in an oil bath to exactly 170°. This temperature is maintained for 30 minutes and then allowed to drop. When the temperature has fallen to 150°, a mixture of 154 g. (1 mole) of pyrogallol-1,3-dimethyl ether and 154 g. (1.1 moles) of hexamethylenetetramine (Note 3) is added as rapidly as possible through the neck holding the thermometer. The temperature drops to approximately 125°. Rapid heating is immediately started but is slowed down when the temperature begins to reach 145° and stopped at 148°. The reaction must be watched and controlled very carefully when this temperature is reached, since the reaction becomes exothermic at this point (Note 4), (Note 5), and (Note 6). The temperature is maintained at 150–160° for approximately 6 minutes (Note 7). At the end of this reaction time the mixture is cooled to 110° as rapidly as possible (Note 6) and (Note , and a previously prepared solution of 184 ml. of concentrated sulfuric acid in 620 ml. of water is added to the reaction mixture. After being stirred for 1 hour, the mixture is cooled to 25° in an ice bath. The boric acid, which separates from the solution, is removed by filtration (Note 9) and washed free of mother liquor with 400 ml. of water. The filtrate and washings are combined and extracted with three 500-ml. portions of chloroform (Note 10), (Note 11), and (Note 12).The chloroform solution is then extracted with a filtered solution of 180 g. of sodium bisulfite in 720 ml. of water (Note 13) by stirring rapidly with a Hershberg stirrer for 1 hour. The separated bisulfite solution is washed twice with chloroform, filtered, and acidified in a hood with a solution of 55 ml. of concentrated sulfuric acid in 55 ml. of water. After careful heating on a steam bath for a short time, air is bubbled through the hot solution until all the sulfur dioxide has been expelled. The product, which separates as a mixture of crystals and oil, readily solidifies upon cooling (Note 14). The syringic aldehyde is collected by filtration, washed with cold water, and dried in an oven at 40° to give 62.5–66 g. of light-tan material, melting at 110.5–111°, which still contains a small amount of foreign material that does not melt at 300°. Recrystallization of the crude product from aqueous methanol using 30 ml. of water and 3 ml. of methanol for each 10 g. of aldehyde gives 56–59 g. (31–32%) of product melting clear at 111–112° (uncor.). A second extraction of the chloroform solution with a filtered solution of 60 g. of sodium bisulfite in 240 ml. of water gives an additional 3–4 g. of product.

I would like to see this formylation on phloroglucinol.

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lugh

the only preparation I could find of the 1,3-dimethyl ether involves the use of gaseous methyl bromide and NaOMe

There is also the distillation of syringic acid to obtain syringol; Ann340 235 (1905); methyl iodide can bee used as an alternative to methyl bromide, and from the trimethyl ether by heating in aqueous or alcoholic alkaline solution

phenethyl_man

... and from the trimethyl ether by heating in aqueous or alcoholic alkaline solution Patent DE162658 ...

I can't find this patent for the life of me.. are you sure you typed it correctly? When I click the link from here it gives a "Document or database inaccessible" error from espacenet. When I try to search for it on esp nothing is found, not even when searched from the german patent office's site. Are you sure that you typed it correctly?

I still need to get to that 1,3-dimethyl ether somehow and I have plenty of both gallic acid and pyrogallol. That patent sounds ideal because then I could just trimethylate pyrogallol, and the patent describes heating in an alkaline solution selectively dealkylates the center methoxyl of 1,2,3-trimethoxybenzene?

Or I guess I could get syringic acid by methylating gallic acid, heating 3,4,5-trimethoxybenzoic acid to 100 degC in 48% HBr for two hours (as described in the JACS article) to cleave the one ether, and then finally that should be able to be decarboxylated since it has a p-hydroxyl group.. Wow, what a pain in the ass to get to such a simple aromatic.. I wonder if heating pyrogallol trimethyl ether in HBr will selectively demethylate also ...?

I would never go thru all that thou.. ah well, maybe I will just find some way to reduce methyl 3,4,5-trimethoxybenzoate to the benzyl alcohol (without LAH). perhaps NaBH4 and NiCl2 in alcohol will do the trick..